The present invention generally relates to novel pharmaceutical compositions for preventing the initiation or transmission of pain signals originating from the peripheral nervous system (xe2x80x9cperipheryxe2x80x9d) to the central nervous system of a mammal and methods for using the compositions, alone or in combination with other therapeutic agents, for the treatment and prevention of symptoms or manifestations associated with the sensation of pain caused by a disease or external stimuli. More particularly, the invention relates to methods for controlling pain transmission by administering at a site where the pain transmission originates a therapeutically effective amount of a pharmaceutical composition comprising anandamide alone, palmitylethanolamide alone or a synergistic mixture of anandamide and palmitylethanolamide. When administered together, these two compounds act synergistically reducing pain more potently than each of them alone.
Analgesics that can effectively control broad levels of pain with a minimum of side effects are being continually sought. Aspirin, the most commonly used analgesic agent, is of no practical value for the control of severe pain and is known to exhibit undesirable side effects. A number of other analgesics, such as d-propoxyphene, codeine and morphine, possess undesirable side effects, such as addictive liability. It is therefore desirable to have compounds and pharmaceutical compositions having improved and potent analgesic properties without undesirable side effects.
Cannabinoids are compounds that are derived from, or chemically related to, the cannabis sativa plant, which is commonly known as marijuana. The most active chemical compound of the naturally-occurring cannabinoids is tetrahydrocannabinol (THC), particularly (xe2x88x92) xcex949-THC (xe2x80x9cTHCxe2x80x9d). Many beneficial pharmacological properties attributed to marijuana include analgesia, lowering blood and intra-ocular pressure, and anti-emetic activity in both human and non-human mammals. Indeed, there has been an ongoing debate over whether marijuana use should be legalized in certain cases, e.g., for use by cancer patients for ameliorating the nausea induced by chemotherapy or to lower pain. Since the discovery of THC, several synthetic cannabinoids have been used clinically for the treatment of cancer patients, among these are: Nabilone, Nabortate and Levonantrodol. However, although these drugs are useful, they possess to some extent the negative pharmacologic properties of THC and thus, are limited in their general use. Notable in the negative properties associated with marijuana and cannabinoids include dependency, psychological distortions of perception, loss of short-term memory, loss of motor coordination, sedation, and euphoria. Compounds that exhibit such negative properties or effects have been referred to as cannabimimetics. Throughout the long history of marijuana, its use and abuse have been intertwined.
It is known that the cannabinoids bind to the so-called CB1 and CB2 receptors in the brain and/or other tissues. Compounds that stimulate the CB1 receptor have been shown to induce analgesia and sedation, to cause mood elevation, to control nausea and appetite and to lower intraocular pressure. Thus, compounds or compositions that stimulate the CB1 or CB2 receptor, directly or indirectly, are useful in treating or controlling pain. In addition to acting at the CB1 and CB2 receptors, however, cannabinoids have been shown to affect cellular membranes, thereby producing undesirable side effects such as drowsiness, impairment of monoamine oxidase function and impairment of non-receptor mediated brain function. These addictive and psychotropic properties of cannabinoids limit their therapeutic value.
It would be beneficial to have an alternate mechanism for stimulating CB1 and CB2 receptors in such a way as to eliminate the undesirable addictive and psychotropic properties of cannabinoids. Accordingly, there remains a need for novel therapeutic compositions and methods that inhibit pain without the above adverse effects and without the attendant disadvantages of conventionally available compounds, including cannabinoid compounds.
It is an object of the present invention to provide novel pharmaceutical compositions and methods useful for inhibiting pain signal initiation and subsequent transmission to the central nervous system in a mammal such that the mammal does not perceive or feel the sensation of pain that it otherwise would have experienced when subjected to pain-causing stimuli.
It is another object of the present invention to provide novel pharmaceutical compositions and methods that are capable of limiting the sensation of pain experienced by a mammal without undesirable side effects.
The above and other objects are accomplished by a pharmaceutical composition comprising a therapeutically effective amount of at least one member of the group consisting of anandamide (xe2x80x9cAEAxe2x80x9d), palmitylethanolamide (xe2x80x9cPEAxe2x80x9d) and derivatives thereof. Anandamide (arachidonylethanolamide) is thought to be produced by enzymatic cleavage of the phospholipid precursor N-acyl phosphatidylethanolamine (Di Marzo, V, et al., Nature 372, 686-691 (1994); Cadas, H., di Tomaso, E. and Piomelli, D., J. Neurosci. 17, 1226-1242 (1997)). Palmitylethanolamide (PEA), which was found in neural and non-neural tissues, has been shown to inhibit mast-cell activation and reduce inflammatory responses (Aloe, L., Leon, A. and Montalcini, R. L., Agents Actions 39, C145 (1993); Mazzari, S., Canella, R., Petrelli, L., Marcolongo, G. and Leon, A., Eur. J. Pharmacol. 300, 227-236 (1996)) by a mechanism that may involve binding to CB2 receptors (Facci, L., et al., Proc. Nat""l. Acad Sci. USA 92, 3376-3380 (1995); Showalter, V. M., Compton, D. R., Martin, B. R. and Abood, M. E., J. Pharmacol. Exp. Ther. 278, 989-999 (1996)).
Anandamide and palmitylethanolamide are readily available compounds that may be obtained via extraction and or purification from sacrificed animals, routine synthesis methods described herein or known in the art or purchased from a suitable commercial supplier. To obtain derivatives, anandamide and palmitylethanolamide may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include, without limitation, those that increase penetration into a given biological compartment, increase bioavailability, increase solubility to allow administration by injection, alter metabolism, alter rate of excretion, etc.
In a further aspect, the present invention is directed to a method for treating pain experienced by in a mammal in need of such treatment, the method comprising:
administering to the mammal a therapeutically effective amount of the pharmaceutical composition of the present invention, wherein said composition is capable of inhibiting pain initiation thereby inhibiting or ameliorating pain experienced by the mammal.
The pharmaceutical compositions and methods of the present invention are characterized by their ability to inhibit pain initiation and/or signaling from the peripheral nervous system to the central nervous system. Specifically, the present invention results in the inhibition of pain signaling that induces the sensation of pain felt by a mammal Without wishing to be bound by theory, it is believed that the pharmaceutical compositions of the present invention short-circuit the intracellular signaling cascade by agonizing CB1- and/or CB2-like receptors found at the periphery of mammals. The present invention regulates pain signaling at the periphery by the activation of local CB1- and CB2-like receptors where it is believed that endogenous cannabinoids participate in filtering and selecting emerging pain signals at sites of tissue injury, a role analogous to that of opioid peptides released from activated immune cells during inflammation. The present invention unexpectedly achieves the above superior and desired effects without the undesired dysphoric side effects and habit-forming properties characteristic of centrally acting cannabimimetic or opiate drugs.
Additional aspects, embodiments and advantages of the present invention will be set forth, in part, in the description that follows, or may be learned from practicing or using the present invention. The objects and advantages may be realized and attained by means of the features and combinations particularly pointed out throughout this description and the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not to be viewed as being restrictive of the invention as claimed.